Selective Alkylation Research Articles

Selective ortho-Functionalization of Adamantylarenes Enabled by Dispersion and an Air-Stable Palladium(I) Dimer.

Contrary to the general belief that Pd‐catalyzed cross‐coupling at sites of severe steric hindrance are disfavored, we herein show that the oxidative addition to C−Br ortho to an adamantyl group is as favored as the corresponding adamantyl‐free system due to attractive dispersion forces. This enabled the development of a fully selective arylation and alkylation of C−Br ortho to an adamantyl group, even if challenged with competing non‐hindered C−OTf or C−Cl sites. The method makes use of an air‐stable PdI dimer and enables straightforward access to diversely substituted therapeutically important adamantylarenes in 5–30 min.

Selectiveortho‐Functionalization of Adamantylarenes Enabled by Dispersion and an Air‐Stable Palladium(I) Dimer

AbstractContrary to the general belief that Pd‐catalyzed cross‐coupling at sites of severe steric hindrance are disfavored, we herein show that the oxidative addition to C−Brorthoto an adamantyl group is as favored as the corresponding adamantyl‐free system due to attractive dispersion forces. This enabled the development of a fully selective arylation and alkylation of C−Brorthoto an adamantyl group, even if challenged with competing non‐hindered C−OTf or C−Cl sites. The method makes use of an air‐stable PdIdimer and enables straightforward access to diversely substituted therapeutically important adamantylarenes in 5–30 min.

Nickel-Catalyzed Alkylation or Reduction of Allylic Alcohols with Alkyl Grignard Reagents.

By choosing different phosphine ligands, nickel-catalyzed selective alkylation and reduction of allylic alcohols with alkyl Grignard reagents were performed. The reaction using Ni(dppe)Cl2 as the catalyst resulted in the cross-coupling of allylic alcohols with primary alkyl Grignard reagents and cyclopropylmagnesium bromide. The reaction catalyzed by the combination of Ni(PCy3)2Cl2 and dcype led to the reduction of allylic alcohols. Secondary alkyl Grignard reagents except cyclopropylmagnesium bromide always led to reduction of allylic alcohols using either Ni(dppe)Cl2 or Ni(PCy3)2Cl2/dcype as the catalyst. In the reductive reaction β-H-containing alkyl Grignard reagents were required.

Catalytic performance of IM-5 zeolite with high xylene selectivity in benzene alkylation with methanol. An alternative to ZSM-5 zeolite

H-ZSM-5, H-IM-5, and H-IM-5(DS) zeolites were synthesized as highly active and shape selective catalysts for the alkylation of benzene with methanol. The samples were characterized by N2-adsorption-desorption, XRD, SEM, TEM, NH3-TPD, and Py-FTIR. The benzene conversion and xylene selectivity were in the same order H-IM-5(DS) > H-IM-5 > H-ZSM-5, while the toluene selectivity was in the reverse order. Combined with the analysis of pore structure and TEM, H-IM-5(DS) zeolite was equipped with more meso/macropores and it exhibited even better catalytic properties. The optimum reaction condition with H-IM-5(DS) as catalysts was obtained.

Shape selective alkylation of benzene with methanol over different zeolite catalysts

Benzene methylation is an important process for removing excess benzene in petrochemical industries to produce value-added products such as toluene and xylene. In this study, the performance of three types of zeolites, which is ZSM-5 (HZ), zeolite Y (HY) and zeolite β (Hβ) were investigated as catalyst in the benzene methylation reaction. The catalysts were characterized by N2 adsorption-desorption and FTIR. The N2 adsorption-desorption verified that the mesopores volume of the catalysts was in the following order: HB > HY > HZ. While, the FTIR-lutidine revealed that the HB possessed the highest amount of Brönsted acid sites followed by HZ and HY. The catalytic testing at 573 K showed that HZ gave good performance in benzene methylation with 55.2% and 22.1% yield of toluene and xylene, respectively. It is suggested that HZ catalyst with moderate amount of Brönsted acid sites and smallest mesopores volume appear to be effective for shape selective synthesis of toluene and xylene. In addition, pore structure of HZ also contributed to the high catalytic activity of benzene methylation.

A unified approach for divergent synthesis of contiguous stereodiads employing a small boronyl group

Acyclic contiguous stereocenters are frequently seen in biologically active natural and synthetic molecules. Although various synthetic methods have been reported, predictable and unified approaches to all possible stereoisomers are rare, particularly for those containing non-reactive hydrocarbon substituents. Herein, a β-boronyl group is employed as a readily accessible handle for predictable α-functionalization of enolates with either syn or anti selectivity depending on reaction conditions. Contiguous tertiary-tertiary and tertiary-quaternary stereocenters are thus accessed in generally good yields and diastereoselectivity. Based on experimental and computational studies, mechanism for syn selective alkylation is proposed, and Bpin (pinacolatoboronyl) behaves as a smaller group than most carbon-centered groups. The synthetic utility of this methodology is demonstrated by preparation of several key intermediates for bioactive molecules.

Ru(II)/Rh(III)-Catalyzed C(sp3)-C(sp3) Bond Formation through C(sp3)-H Activation: Selective Linear Alkylation of 8-Methylquinolines and Ketoximes with Olefins.

Herein, [RuCl2(p-cymene)]2/[Cp*RhIIICl2]2-catalyzed direct alkylation of C(sp3)-H bond of 8-methylquinolines with olefins (acrylates, styrenes, and aliphatic) is reported. The alkylation also proceeds with other conjugated systems such as malemides and α,β-unsaturated ketones. The reaction is highly regioselective, forms only a linear product, and tolerates a variety of functional groups on quinoline and olefin moieties. Control experiments, deuterium labeling, and kinetic studies have been carried out for preliminary understanding of the reaction pathway. The reaction possibly proceeds through five-membered metallacycle under redox-neutral condition. Diversification of alkylated product and late-stage functionalization of ketoxime derivatives of (-)-santonin have also been carried out to demonstrate the applicability of the developed method.

Analysis of decisive structural parameters of zeolites for alkylation of benzene with ethylene

The effects of the zeolite structure and the Brønsted and Lewis sites on the activity and selectivity in alkylation of benzene with ethylene to ethylbenzene were investigated using three series of zeolites with different structures, Si/Al ratios and contents of Lewis sites. The 12-membered three-dimensional channels of beta zeolite (*BEA) provide higher selectivity to ethylbenzene compared to faujasite zeolite (FAU) with cavities in which the di-alkylated and heavier by-products are formed. The activity is controlled by the concentration of Brønsted acidic sites, while Lewis sites do not contribute to the activity or affect the selectivity. The highest activity and selectivity are obtained using Al-rich H-*BEA (Si/Al 4.2) with a high density of Brønsted groups in a well-defined channel structure sterically constrained for heavy by-products. It is shown that a three-dimensional channel structure with Brønsted acid sites in a shape selective environment is a key parameter controlling the activity and selectivity.

Site-Selective, Modular Diversification of Polyhalogenated Aryl Fluorosulfates (ArOSO2 F) Enabled by an Air-Stable PdI Dimer.

Since 2014, the interest in aryl fluorosulfates (ArOSO2F) as well as their implementation in powerful applications has continuously grown. In this context, the enabling capability of ArOSO2F will strongly depend on the substitution pattern of the arene, which ultimately dictates its overall function as drug candidate, material, or bio‐linker. This report showcases the modular, substrate‐independent, and fully predictable, selective functionalization of polysubstituted arenes bearing C−OSO2F, C−Br, and C−Cl sites, which makes it possible to diversify the arene in the presence of OSO2F or utilize OSO2F as a triflate surrogate. Sequential and triply selective arylations and alkylations were realized within minutes at room temperature, using a single and air‐stable PdI dimer.

Organo Photoinduced Decarboxylative Alkylation of Coumarins with N-(Acyloxy)phthalimide.

A metal-free and mild, photoinduced decarboxylative 4-position alkylation of coumarins has been reported. Photoinduced single electron transfer has been initiated by utilizing the visible-light absorptivity of Eosin Y for a reductive generation of alkyl radicals from N-(acyloxy)phthalimide esters. Depending on the nature of N-(acyloxy)phthalimide esters (primary, secondary, and tertiary carboxylic acid derived), several saturated and unsaturated C-4 alkylated coumarins were synthesized. Both control experiments and photophysical studies supported a radical based mechanism for the selective alkylation.

Antimicrobial Polymer with Enhanced Activity and Reduced Toxicity upon Grafting to Chitosan Oligosaccharide

The aim of this work was to develop a novel, nontoxic, bioactive antimicrobial material based on a natural polymer, chitosan oligosaccharides (COS), a natural pyrone compound, kojic acid (KA), and piperazine. The COS-based polymer (COS-O-MB) has been synthesized by selective partial alkylation reaction to graft kojic acid, KA, and piperazine onto the COS molecular chain. Then, physicochemical properties and bioactivity of the COS-O-MBs were evaluated and it was characterized by FT-IR, NMR spectroscopy, Mw, PID, antimicrobial activity, hemolysis assay, biocompatibility, animal toxicity, and antimicrobial action mode studies. The results revealed that the alkylation reaction took place at the C-6 position of COS, and the as-prepared COS-O-MB significantly enhanced the antimicrobial activity and biocompatibility and reduced the hemolytic activity in vitro in comparison with that of the free COS and KA. Meanwhile, the antimicrobial action mode studies proved that COS-O-MB can pass through the anionic microbial membrane, destroy the cytomembrane integrity, and potentially affect protein denaturation, demonstrating that exposure to COS-O-MB results in the death of microbial cells. But importantly, COS-O-MB is not toxic to human cells. Hence, low hemolytic activity to human red blood cells, and nontoxic nature to female mice of SLAC KM strain, made this novel polymer material a promising and effective compound for food and pharmaceutical industries.

The Electrogenerated Cyanomethyl Anion: An Old Base Still Smart.

The cathodic reduction of acetonitrile solutions containing a tetraalkylammonium salt leads to the formation of the cyanomethyl anion (-CH2CN, cyanomethanide). This electrolysis can be carried out under very simple experimental conditions (constant-current electrolyses), using various cathodic materials, controlling the amount of base by simply controlling the amount of charge. Despite the fact that the mechanism for this electrochemical reaction is still debated (and it depends on the cathodic material), the outcome of the electrolysis is the formation of a strong base, -CH2CN (pKa 31.3 for acetonitrile in DMSO). The chemical behavior of this electrogenerated base (EGB) strongly depends on its counterion, which in this case is a tetraalkylammonium cation, with a low charge density and thus not coordinated. The very weak interaction between R4N+ and -CH2CN renders the cyanomethyl anion a "naked" ion, and thus highly reactive. In particular, the cyanomethyl anion can react as a base and as a nucleophile. In the first case, it behaves as a strong base and, after deprotonation of a weak acidic substrate, transforms itself into a solvent molecule, acetonitrile, thus generating no byproducts. In the second case, the reactivity as a nucleophile of the cyanomethyl anion obviously depends on the reaction partner. When an electrophile is present in the reaction mixture, a cyanomethylation is obtained (e.g., with aromatic aldehydes, possessing no acidic hydrogen atoms, which undergo nucleophilic attack on the carbonyl carbon atom by -CH2CN); on the contrary, when no reagent is present other than acetonitrile and tetraalkylammonium salt, an attack on the parent molecule leads to the acetonitrile dimer, 3-aminocrotononitrile, which in turn can behave as a base and/or as a nucleophile. In this regard, some authors report that it is preferable to carry out the electrogeneration of the cyanomethyl anion under different experimental conditions, i.e., using an undivided cell and a sacrificial magnesium anode. In this way, a Grignard-type reagent is formed (Mg(CH2CN)2) which highly stabilizes the cyanomethyl anion, preventing its dimerization. It should be noted that in our laboratory the electrogenerated tetraalkylammonium cyanomethanide was extensively used in various reactions (both acid-base and nucleophile-electrophile, vide infra), and in almost no case, the amount of acetonitrile dimer formed exceeded 5%, confirming the validity of this electrochemical methodology to generate a very efficient base. Moreover, when in the reaction mixture both a weak acid and an electrophile are present, the prevalent reactivity of the cyanomethyl anion is as a base, leaving the possibility of a cyanomethylation reaction to those cases in which no acidic substrate is present. We have successfully used the electrogenerated cyanomethyl anion in many base-induced reactions, as the synthesis of the β-lactam ring (chiral or not), the insertion of carbon dioxide into amines and amino alcohols, the activation of elemental sulfur and insertion into carbonyl compounds, the selective alkylation of difunctional compounds, etc.

Scandium-Catalyzed para-Selective Alkylation of Aromatic Amines with Alkenes.

An efficient para-alkylation of primary and secondary anilines with a variety of sterically encumbered alkenes using a simple β-diketiminato scandium catalyst is reported. This protocol features 100% atom economy, excellent chemo- and regioselectivity, broad substrate scope, and good functional group tolerance. Mechanistic studies disclosed that the reaction probably proceeded via a tandem hydroamination/Hofmann-Martius rearrangement.

Hydrogen transfer-mediated selective dual C–H alkylations of 2-alkylquinolines by doped TiO2-supported nanocobalt oxides

Alkylquinolines are ubiquitous in functional products. However, the direct and selective alkylation of quinolines has to date remained a challenge. Herein, by developing a new catalyst composing of cobalt oxides supported on N-Si-doped titanium dioxide (CoOx/N-Si-TiO2), we present, for the first time, its application toward hydrogen transfer-mediated dual β-alkylations of 2-alkylquinolines with various aldehydes. The developed chemistry allows a direct access to a wide array of 2,3-dialkylquinolines in conjunction with the features of good substrate and functional group compatibility, high regio and chemoselectivity, the use of naturally abundant and reusable heterogeneous cobalt catalyst, and the generation of H2O as the by-product, which has demonstrated the potential in direct functionalization of multiple heteroaryl CH bonds by the combination of heterogeneous catalyst design with reductive dearomatization as an activating mode of N-heteroarenes.

Redox properties of individual quercetin moieties

Quercetin is one of the most prominent and widely studied flavonoids. Its oxidation has been previously investigated only indirectly by comparative analyses of structurally analogous compounds, e.g. dihydroquercetin (taxifolin). To provide direct evidence about the mechanism of quercetin oxidation, we employed selective alkylation procedures for the step-by-step blocking of individual redox active sites, i.e. the catechol, resorcinol and enol C-3 hydroxyls, as represented by newly prepared quercetin derivatives 1–3. Based on the structure-activity relationship (SAR), electrochemical, and computational (density functional theory) studies, we can clearly confirm that quercetin is oxidized in the following steps: the catechol moiety is oxidized first, forming the benzofuranone derivative via intramolecular rearrangement mechanism; therefore the quercetin C-3 hydroxy group cannot be involved in further oxidation reactions or other biochemical processes. The benzofuranone is oxidized subsequently, followed by oxidation of the resorcinol motif to complete the electrochemical cascade of reactions. Derivatization of individual quercetin hydroxyls has a significant effect on its redox behavior, and, importantly, on its antiradical and stability properties, as shown in DPPH/ABTS radical scavenging assays and UV–Vis spectrophotometry, respectively. The SAR data reported here are instrumental for future studies on the oxidation of biologically or technologically important flavonoids and other polyphenols or polyhydroxy substituted aromatics. This is the first complete and direct study mapping redox properties of individual moieties in quercetin structure.

Reactive OFF-ON type alkylating agents for higher-ordered structures of nucleic acids.

Higher-ordered structure motifs of nucleic acids, such as the G-quadruplex (G-4), mismatched and bulge structures, are significant research targets because these structures are involved in genetic control and diseases. Selective alkylation of these higher-order structures is challenging due to the chemical instability of the alkylating agent and side-reactions with the single- or double-strand DNA and RNA. We now report the reactive OFF-ON type alkylating agents, vinyl-quinazolinone (VQ) precursors with a sulfoxide, thiophenyl or thiomethyl group for the OFF-ON control of the vinyl reactivity. The stable VQ precursors conjugated with aminoacridine, which bind to the G-4 DNA, selectively reacted with a T base on the G-4 DNA in contrast to the single- and double-strand DNA. Additionally, the VQ precursor reacted with the T or U base in the AP-site, G-4 RNA and T-T mismatch structures. These VQ precursors would be a new candidate for the T or U specific alkylation in the higher-ordered structures of nucleic acids.

Radical coupling from alkyl amines

Radical intermediates are key species in many chemical transformations. Recent advances have provided a new suite of selective radical alkylation reactions. This Comment highlights pioneering studies using alkyl amines that act as radical precursors in a number of catalytic processes by their conversion to alkylpyridinium salts.

Directing-Group-Free C7-Alkylations of N-Alkylindoles Mediated by Cationic Zirconium Complexes: Role of Brønsted Acid for Catalytic Manifold.

Highly position selective alkylations of N-alkylindoles at C7-positions have been enabled by cationic zirconium complexes. The strategy provides a straightforward access to install alkyl groups at C7-positions of indoles without a complex directing group. Mechanistic studies provided support for the importance of Brønsted acids in the catalytic manifold.

Nucleophilic Substitution of Aliphatic Fluorides via Pseudohalide Intermediates

A method for aliphatic fluoride functionalization with a variety of nucleophiles has been reported. Carbon-fluoride bond cleavage is thermodynamically driven by the use of silylated pseudohalides TMS-OMs or TMS-NTf2 , resulting in the formation of TMS-F and a trapped aliphatic pseudohalide intermediate. The rate of fluoride/pseudohalide exchange and the stability of this intermediate are such that little rearrangement is observed for terminal fluoride positions in linear aliphatic fluorides. The ability to convert organofluoride positions into pseudohalide groups allows facile nucleophilic attack by a wide range of nucleophiles. The late introduction of the nucleophiles also allows for a wide range of functional-group tolerance in the coupling partners. Selective alkyl fluoride mesylation is observed in the presence of other alkyl halides, allowing for orthogonal synthetic strategies.

Synthesis, Characterization, and Anticancer Activities Evaluation of Compounds Derived from 3,4-Dihydropyrimidin-2(1H)-one.

3,4-dihydropyrimidin-2(1H)-one compounds (DHPMs) possess extensive biological activities and are mainly prepared via Biginelli reaction and N-alkylation. In the present study, selective alkylation of N1 was investigated by using tetrabutylammonium hydroxide. In vitro cytotoxicity study on all synthesized compounds demonstrated that introduction of the aryl chain in the R3 as well as the low electron-donating group in the R1 of DHPMs contributed to the anti-proliferative potency. A larger value of the partition coefficient (Log P) and suitable polar surface area (PSA) values were both found to be important in order to maintain the antitumor activity. The results from in vivo study indicated the great potential of compound 3d to serve as a lead compound for novel anti-tumor drugs to treat glioma. Pharmacophore study regarding the structure-activity relations of DHPMs were also conducted. Our results here could provide a guide for the design of novel bioactive 3,4-dihydropyrimidin-2(1H)-one compounds.